tbuckley/cabot-search huggingface dataset:
OReO/ENGOT Ov-38 trial: Impact of maintenance olaparib rechallenge according to ovarian cancer patient prognosis—An exploratory joint analysis of the BRCA and non-BRCA cohorts.
Authors: Frederic Selle, Bernard Asselain, François Montestruc, Fernando Bazan, Beatriz Pardo, Vanda Salutari, Frederik Marmé, Anja Ør Knudsen, Alessandra Bologna, Radoslaw Madry, Rosalind Glasspool, Stéphanie Henry, Jacob Korach, Stephanie Lheureux, Bob Shaw, Ana Santaballa, Raffaella Cioffi, Ulrich Canzler, Alain Lortholary, Eric Pujade-Lauraine
Journal: Journal of Clinical Oncology (2022)

5558 Background: In the Phase IIIb OReO/ENGOT Ov-38 trial (NCT03106987), maintenance olaparib (O) rechallenge significantly improved progression-free survival (PFS) vs placebo in patients (pts) with platinum-sensitive relapsed ovarian cancer (PSROC) regardless of their BRCA status (Pujade-Lauraine, ESMO 2021). The impact of prognostic factors on this PFS benefit were unknown. Methods: Pts had PSROC, one prior line of PARP inhibitor (PARPi) maintenance and were in response to platinum-based chemotherapy (Cx). Pts were enrolled into two cohorts – BRCA mutated (BRCAm) and non-BRCAm – and randomized to receive maintenance O (300 mg bid) or placebo. Primary endpoint was PFS. Post-hoc individual patient data meta-analysis was used to combine both cohorts using fixed and random effect models, interaction, and stratified tests in the Cox model. Stepwise Cox multivariate model for PFS and logistic regression models were used for late relapse, defined as disease progression occurring &gt;24 weeks after randomization. Randomization stratification criteria and cohort effect were included in all models. Results: This study included 220 pts from the BRCAm (n=112) and non-BRCAm (n=108) cohorts recruited between October 3, 2017 and February 10, 2021. No heterogeneity was detected between cohorts: Cochran’s Q test P=0.53 (fixed and random); interaction test P=0.63. The O effect was consistent, and no significant interactions were observed between subgroups. In the multivariate PFS analyses, the main independent factors for prognosis were CA-125 level, visceral disease (liver, lung, pleura, brain), and treatment arm. These factors were independent predictive factors for late relapse among the 181 evaluable pts with the opportunity of at least 6 months of follow-up (Table). Conclusions: In the OReO/ENGOT Ov-38 trial, CA-125 level and presence of visceral disease at baseline were the best predictors of patient outcome. Maintenance olaparib rechallenge was effective overall regardless of prognostic subgroup. Clinical trial information: NCT03106987. [Table: see text]
Exploratory hrd and PD-L1 analysis of l-MOCA study: Olaparib maintenance monotherapy in Asian patients with platinum-sensitive relapsed ovarian cancer.
Authors: Ding Ma, Qing-lei Gao, Jianqing Zhu, Weidong Zhao, Yi Huang, Ruifang An, Hong Zheng, Pengpeng Qu, Li Wang, Qi Zhou, Danbo Wang, Ge Lou, Jing Wang, John Low, Beihua Kong, Rutie Yin, Xing Xie, Jihong Liu, Wei Sun, Rongyu Zang
Journal: Journal of Clinical Oncology (2022)

e17578 Background: Olaparib demonstrated its efficacy to prolong progression-free survival (PFS) in platinum-sensitive relapsed ovarian cancer (PSROC) patients (L-MOCA study). Almost half of OC patients harbor homologous recombination deficiencies (HRD). However, there is lack of the HRD prevalence in Asian PSR population. Meanwhile, Immunological processes play a key role in tumorigenesis and PD-L1 status may hinder an effective antitumor immune response in OC. Herein, we analyzed HRD and PD-L1 status in Asian patients with PSROC, and explored Olaparib response to different HRD status. Methods: In this exploratory analysis of L-MOCA trial, HRD and PD-L1 status were analyzed from patients with PSROC. Residual DNA samples of 193 patients were analyzed for HRD status with a local developed HRD assay (Teddy Laboratory, Shanghai, China, which determines two major components, tBRCA1/2 status and LOH score, HRD positive indicates the presence of a deleterious or suspected deleterious BRCA mutation or LOH score ≥0.4). The remaining formalin fixation and paraffin embedded samples were used for PD-L1 expression analysis by immunohistochemistry with SP263. Descriptive statistics were summarized for HRD status, PD-L1 expression status and PFS by different HRD status subgroups. Results: 193 of 224 patients had residual DNA for HRD test. Patients clinical characteristics were similar between those with and without residual DNA for HRD test, in terms of age (mean age 55.5y Vs 54.2y), FIGO stage (stage III 68.9% Vs 61.3%, stage IV 12.4% Vs 22.65%), and time to disease progression to Last prior Platinum Based Chemotherapy (6-12m: 39.9% Vs 41.9%; &gt; 12m: 59.6% Vs 54.8%). Among 193 patients with HRD test conducted, proportion of HRD+ BRCAm, HRD+ BRCAwt, HRD- and HRD unknown were 37.3%, 28.0%, 14.5% and 20.2%, separately. mPFS of the above subgroups was 20.1 months, 15.8 months, 9.2 months and 16.4 months, respectively (Table1). 200 of 224 patients were available for PD-L1 expression analysis. 184 (92%) with TC＜1%, 12 (6%) with TC among 1-25%. These results showed TC expression in all patients were less than 25%, suggesting that ovarian cancer may be an immunologically cold tumor. Conclusions: This is firstly showing the HRD and PD-L1 status in Asian OC patients. The results showed all the PSR patients could benefit from Olaparib treatment, regardless of HRD status. Meanwhile the numerically different mPFS observed across different HRD status subgroups also indicated potential clinical utility of locally developed HRD assay. Clinical trial information: NCT03534453. [Table: see text]
Survival analysis of patients with early and standard onset colorectal cancer: A single center study.
Authors: Dhruv Patel, Catarina Martins Maia, Michael Lyudmer, Seda Tolu, Adel Chergui, Riya Jayesh Patel, So Yeon Kim, Radhika Gali, Ana Acuna Villaorduna, Sanjay Goel
Journal: Journal of Clinical Oncology (2022)

e15512 Background: While more aggressive clinical/pathological features have been consistently described in between patients with early-onset (EO) and standard-onset (SO) colorectal cancer (CRC), survival data have been conflicting. While some studies report better survival rates for EO-CRC; others found that outcomes among groups are not different. In a prior study, using the Surveillance, Epidemiology and End Results (SEER), we reported that cancer-related survival did not differ between EO-CRC and SO-CRC; however, a main limitation was the lack of molecular status and treatment details among groups. This study aims to compare the survival of EO-CRC and SO-CRC patients at Montefiore Medical Center. Methods: Retrospective cohort among 690 patients diagnosed with metastatic colorectal cancer (CRC) at Montefiore Medical Center between 2010 and 2018. Patients were identified using the software Clinical Looking Glass and charts were reviewed manually to gather information about demographics (race/ethnicity defined as Non-Hispanic White [NHW], Non-Hispanic Black [NHB] and Hispanic [H], gender, comorbidity index, calculated using the Charlson comorbidity score), clinicopathological features (grade, tumor sidedness, K-ras mutation) and treatment-related characteristics (metastatectomy, lines of chemotherapy and use of biologics). EO-CRC was defined as CRC diagnosis before age 50 and SO-CRC as CRC diagnosed at 50 years or older. Overall survival was compared between EO-CRC and SO-CRC using Kaplan Meier and Cox regression analyses. Stata v15.1 was used for statistical analysis. Results: Of 690 patients with CRC, 139 (20.1%) had EO-CRC and 551 (79.9%) had SO-CRC. Participants with EO-CRC had a higher frequency of poorly-differentiated tumors (35.5% vs. 23.8%, p = 0.02), a lower comorbidity index (6 vs. 7, p &lt; 0.001). and a higher use of biologics (70.5% vs. 60.8%, p = 0.03) compared to SO-CRC. K-ras mutation was available for 377 (54.5%) of cases and did not differ among groups (45.9% vs. 45.9%, p = 0.99). In a model adjusted for race/ethnicity, gender, comorbidity index, sidedness, use of biologics and metastatectomy, there was no difference in mortality among groups (HR:0.9, 95%CI: 0.58 – 1.43, p = 0.68). This result remained unchanged in a model restricted to patients with available K-ras-status (n = 75), adjusted for all these variables. Conclusions: Despite more aggressive clinical/pathological features in patients with EO-CRC, survival does not differ compared to SO-CRC.
Efficacy of hyperthermic-intra-vesical chemotherapy in patients with BCG-refractory nonmuscle-invasive bladder cancer.
Authors: Geraldine Pignot, Vito Lorusso, Laure Doisy, Mathilde Guerin, Cecile Vicier, Slimane Dermeche, Nicolas Branger, Thomas Maubon, Stanislas Rybikowski, Jochen Walz, Gwenaelle Gravis
Journal: Journal of Clinical Oncology (2022)

4592 Background: In Bacillus Calmette-Guérin (BCG) refractory non-muscle-invasive bladder cancer (NMIBC), radical cystectomy is the standard of care. For patients unwilling or unable to undergo cystectomy, alternative intravesical therapies are currently being investigated to minimize the risk of recurrence and progression. Chemohyperthermia by HIVEC (Hyperthermic-Intra-Vesical Chemotherapy) is a therapeutic option in BCG-refractory patients. The objective of our study was to evaluate the 2-year oncological results of HIVEC in BCG-refractory patients. Methods: Between June 2016 and September 2021, patients treated with HIVEC (6 weekly instillations) for BCG-refractory NMIBC were prospectively included in our study. These patients had a theoretical indication for cystectomy but were ineligible for surgery or refused it. The primary endpoint was 1-year recurrence-free survival (RFS) rate. Secondary endpoints were 6-month complete response rate for Cis, 1-year overall and cancer-specific survival rates and bladder preservation rate. Results: Seventy patients, mean age 70 [42-89] years, were treated consecutively. After a mean follow-up of 20.9 months, 32 patients recurred (mean time of 10.6 months) and 7 patients finally had a cystectomy. The recurrence-free survival rate was 53.1% at 1 year and 20.5% at 2 years. Six patients progressed to a muscle-invasive disease, after a mean delay of 6.7 months. Four of them experienced metastatic progression and died from bladder cancer. Cancer-specific and overall survival rates were 95.1% and 92.9% at 1 year, and 87.5% and 77.8% at 2 years. The bladder preservation rate was 90%. For patients with Cis (34% of the entire series), the 6-month complete response rate was 75%. The presence of Cis was not a predictive factor of response to HIVEC. Tolerance was excellent with 38.2% grade 1-2 adverse events and no grade 3-4 adverse events. Conclusions: Chemohyperthermia using the HIVEC device achieved a RFS rate of 53.1% at 1 year and enabled a bladder preservation rate of 90%. While cystectomy remains the standard of care, HIVEC may be discussed cautiously for patients who are not eligible for surgery and well informed of the risk of progression to muscle-invasive disease.
A phase II study evaluating the efficacy of niraparib and dostarlimab (TSR-042) in recurrent/metastatic head and neck squamous cell carcinoma.
Authors: Vidhya Karivedu, Muhammad Kashif Riaz, Maria Mathews, Nicky Kurtzweil, Ilaina Monroe, Audrey Romano, Trisha Michel Wise-Draper
Journal: Journal of Clinical Oncology (2022)

TPS6105 Background: Despite improvement in outcomes with checkpoint (PD-1) inhibitors in some patients (pts) with recurrent and metastatic head and neck squamous cell carcinoma (RM HNSCC), overall survival (OS) remains poor, necessitating novel therapy combinations. Fanconi Anemia (FA) and FA-related DNA repair pathways alterations have been associated with cumulative tumor mutational burden (TMB) due to genomic instability. High TMB is associated with improved response to PD-1 inhibitors. DNA pathway repair mutations have been reported in 17% of sporadic HNSCC. Ataxia-Telangiesctasia Mutated (ATM) loss has been reported in 60% of human HNSCC biopsies and FA-related defects were reported in 15-21% of human HNSCC biopsies and cell lines. Poly (ADP-ribose) polymerase (PARP) inhibition has already demonstrated efficacy as a single agent in multiple cancers which harbor a DNA repair defect. Preclinical data also showed PARP inhibitor (PARPi) upregulates PD-L1 expression in cancer lines and animal models via inactivation of glycogen synthase kinase 3 (GSK3β). Importantly, blockade of PD-1 re-sensitized PARPi treated cells to induce T-cell mediated cytotoxicity. Combination of PARPi and anti-PD-1 therapy significantly increased therapeutic efficacy in vivo compared to single agent. Therefore, we hypothesized that the combination of a PARPi (niraparib) and PD-1 blockade (dostarlimab) in our ongoing phase II study would enhance overall response (OR) and survival in R/M HNSCC pts (NCT04313504). Methods: Eligible pts must have a confirmed histopathology of non-cutaneous RM HNSCC not amenable to local therapy, progressive disease (PD) after at least one line of platinum-based chemotherapy and/or immunotherapy, age&gt;18, ECOG &lt;2, no prior therapy with PARPi and adequate bone marrow, liver, and renal function. Seven of 14 pts have been enrolled in the first stage of the study. If 8 or more pts develop either stable disease (SD), partial (PR) or complete response (CR), 9 additional patients will be accrued for a total of 23 patients. Pts will receive 200 mg PO niraparib daily in 28-day cycles along with dostarlimab 500mg (Q3W) for 4 doses followed by 1000mg (Q6W) until PD or unacceptable toxicity. An interim analysis will be performed to assess efficacy and safety after 14 patients become evaluable. Tumor response will be assessed per RECIST v1.1. Primary endpoint is best OR including SD, PR, and CR; Secondary endpoints include adverse events determined by CTCAE v5.0, progression free survival and OS. Integrated tissue analysis includes DNA pathway repair defects and TMB. Additional exploratory analyses including peripheral and immune cell activation will be performed on tissue and plasma samples. Clinical trial information: NCT04313504.
An ultra-sensitive assay using cell-free DNA fragmentomics for multi-cancer early detection.
Authors: Yang Shao, Hua Bao, Zheng Wang, Xiaoji Ma, Wei Guo, Xiangyu Zhang, Xinyu Wang, Yikuan Chen, Shaobo Mo, Naixin Liang, Qianli Ma, Yaqi Li, Long Zhang, Fengwei Tan, Qi Xue, Fangqi Liu, Sanjun Cai, Shugeng Gao, Junjie Peng, Jian Zhou
Journal: Journal of Clinical Oncology (2022)

3037 Background: Although most cancer can benefit from early detection by more effective treatments and better prognosis, current screening programs are only limited to tumor-specific tests for a subset of common cancers. To benefit a broader population and outweigh the risks of single-cancer tests, an effective and affordable multi-cancer test should be developed for sensitive early detection of multiple cancers and accurate prediction of cancer tissue of origin simultaneously. Methods: In this study, we enrolled 971 cancer patients of the most prevalent and lethal cancer types, including primary liver cancer (PLC, N= 381), colorectal adenocarcinoma (CRC, N= 298), and lung adenocarcinoma (LUAD, N= 292), as well as 243 healthy controls. The participants were randomly divided into a training cohort and a test cohort in a 1:1 ratio. Five fragmentomic features representing cfDNA fragmentation size, motif sequence, and copy number variation were extracted from processed whole-genome sequencing (WGS) data of the participants to build the base models. Each base model implemented five machine learning algorithms for model training, and the optimal base models were used to create the final multi-dimensional model through ensemble stacked machine learning. The integrated multi-cancer model is composed of the first-level binary cancer detection model and the second-level multi-classification cancer origin model. The training cohort was used to train the models with 10-fold cross-validation. The test cohort remained untouched during model construction and was solely used for performance evaluation. Results: Our cancer samples are highlighted by mostly early-stage diseases (early-stage PLC: 88.5%; CRC: 100.0%; LUAD: 100.0%). The cancer detection model reached an area under the curve (AUC) of 0.983 for differentiating cancer patients from healthy individuals in the test cohort. At 95.0% specificity, the sensitivity of detecting all cancer is 95.5%, and 100.0%, 94.6%, and 90.4% for PLC, CRC, and LUAD, respectively. Its sensitivity is consistently high for early-stage, small-size tumors. The cancer origin model demonstrated an overall 93.1% accuracy for predicting tissue of origin in the test cohort (97.4%, 94.3%, and 85.6% for PLC, CRC, and LUAD, respectively). Furthermore, the model's cancer detection and origin classification performance remained robust when reducing sequencing depth to 1× (cancer detection: ≥ 91.5% sensitivity at 95.0% specificity; cancer origin: ≥ 91.6% accuracy). Conclusions: We utilized multiple plasma cfDNA fragmentomic features to build an ensemble stacked machine learning model. The assay reached ultrasensitivity and accuracy for multi-cancer early detection, shedding light on leveraging cfDNA fragmentomics for early screening in clinical practice.
Immune-related adverse events and immunotherapy efficacy in patients with cancer: A retrospective study.
Authors: Lyndsey L Prather, Atif Ali, Hannah Wang, Wendy Du, Nan Chen, Aakash Sheth, Vlad Sandulache, Anita Lyn Sabichi, Jan Ole Kemnade, Daniel Ying Wang
Journal: Journal of Clinical Oncology (2022)

2654 Background: Immune checkpoint inhibitors are revolutionizing cancer care and providing new treatment options with promising outcomes for many cancers. However, immune-related adverse events (irAEs) are not infrequent and can be severe. An intriguing relationship between the presence of irAEs and treatment efficacy has been described but lacks thorough characterization. We aimed to further elucidate a relationship between immune checkpoint inhibitor (ICI) irAEs and efficacy. Methods: We identified cancer patients treated with ICI from 2015-2021 across two institutions: Michael E DeBakey Veterans Affairs Medical Center (MEDVAMC) and Baylor St. Luke’s Medical Center (BSLMC). Clinical data including cancer type, irAEs type and grade, ICI response, progression free survival (PFS) and overall survival (OS) was collected. Using the Kaplan Meier method, survival curves were generated and comparisons were made amongst groups using the log-rank test. Fisher’s exact test was used to compare progression of disease between groups. To determine if variables were associated with survival, multivariable Cox regression analysis was used. Results: Of the 456 patients treated with ICI, irAEs were seen in 165 (36%) patients. Of these, 81 (49%) patients had grade 1 toxicities, most commonly arthritis, diarrhea, and dermatitis. 47 (28%) patients had grade 2 toxicities (colitis, hypothyroidism, adrenal insufficiency). 34 (21%) patients had grade 3 toxicities (pneumonitis, pancreatitis, hepatitis). 3 patients had grade 4 toxicities (pneumonitis, DRESS syndrome, and hepatorenal syndrome). 1 patient expired and 24 (15%) patients discontinued ICI due to irAEs. 55 (33%) of patients with irAEs were treated with steroids. For patients assessed for efficacy, objective response rate (ORR) to ICI was higher in patients with irAEs [47% (12% CR) vs 33% (11% CR)]. In fact, the presence of any irAEs was significantly likely to predict response to ICI (OR 1.90, 95% CI 1.25 - 2.86, p = 0.0026). In a subset of patients evaluable for survival (n = 375), patients with any irAEs had a significantly improved median PFS compared to those without irAEs (9.0 vs. 4.8 months, p = 0.0018). Multivariable analysis demonstrated that the development of any irAEs was related to a significantly improved OS (HR 0.63, 95% CI 0.43-0.89, p = 0.01). Conclusions: The development of irAEs in cancer patients treated with immunotherapy may predict better treatment efficacy and overall survival. Further prospective studies are needed to confirm these associations and mechanism of action.
Predictors of immunotherapeutic benefits in patients with advanced melanoma and other malignancies treated with immune checkpoint inhibitors utilizing ORIEN “real-world” data.
Authors: Ahmad A. Tarhini, Aik Choon Tan, Mengyu Xie, Issam El Naqa, Payman Ghasemi Saghand, Donghai Dai, James Lin Chen, Aakrosh Ratan, Martin McCarter, John D. Carpten, Howard Colman, Alexandra Ikeguchi, Abhishek Tripathi, Igor Puzanov, Susanne M. Arnold, Michelle L. Churchman, Patrick Hwu, Jose Conejo-Garcia, William S. Dalton, George J. Weiner
Journal: Journal of Clinical Oncology (2022)

2618 Background: Despite the significant improvements in treating cancer with immune checkpoint inhibitors (ICIs), many patients (pts) do not achieve disease control. Using Oncology Research Information Exchange Network (ORIEN) Avatar real-world data conducted under the Total Cancer Care protocol we investigate predictive biomarkers of ICI benefits in pts with advanced malignancies. Methods: Clinical data were normalized as part of ORIEN Avatar. RNA-seq was performed on tumor samples following the RSEM pipeline and gene expressions were quantified as Transcript Per Million (TPM). Gene expressions (GE) were log2(TPM+1) transformed. Mann-Whitney U-test was used to compute differences between groups, and Kaplan-Meier survival analysis was performed. Results: Pts (n=1214) with 27 cancer types treated with ICIs were retrieved from the database, where 1143 and 875 patients were profiled by WES and RNA-seq, respectively. 804 pts had both WES and RNA-seq data. The top six cancer types were renal cell carcinoma (n=206), non-small cell lung cancer (n=173), head and neck cancer (n=157), melanoma (n=154), sarcomas (n=99) and bladder cancer (n=87). The ICI regimens included therapy with atezolizumab (n=87), avelumab (n=12), cemiplimab (n=6), ipilimumab (n=47), nivolumab (n=424), pembrolizumab (n=525) and ipilimumab+nivolumab (n=113). Median overall survival (OS) for the entire cohort was 21.9 months. Patients had significant improvement in OS if ICI was given in the first line ( P&lt;0.0001). Previously published GE signatures were tested in the melanoma cohort. Signatures related to IFNg, effector T cells, chemokines, MHC II and Tertiary Lymphoid Structures were significantly prognostic and predictive of ICI benefits in advanced melanoma (Table). Analyses in the other cancer types are ongoing. Conclusions: GE data analyses validate the predictive value of immune related gene signatures following ICI immunotherapy in melanoma. Ongoing analyses are investigating these signatures in other malignancies and integrating the GE data with data related to TMB, somatic mutations and germline genetic variations.[Table: see text]